Therapeutic activation of AMPK for the aging right heart

摘要/项目摘要 这个应用程序的首要目标是为布鲁斯博士提供科学和职业生涯 在心脏老化领域发展成功的独立研究事业，具有 特别集中在右脑室。心力衰竭(HF)是一个主要的公共卫生问题 人口老龄化。在年龄相关的左心衰以及其他临床情况下，右 室壁(RV)功能障碍是死亡率的最强预测因子。然而，尽管有明确的 右心功能与生存之间的联系，对右心功能与年龄的关系知之甚少。 这一知识差距突出了评估老化对房车的影响的必要性 开发针对RV功能下降的治疗药物的长期目标。虽然没有房车- 我们实验室的流行病学数据和初步数据表明，定向治疗是存在的 AMP激活蛋白激酶(AMPK)的激活可能通过新的和直接的 对心脏收缩装置的作用。因此，这个项目的全球假设是 衰老加剧了右室功能障碍，而收缩装置介导的机制可能是 为老化的右心开发新的治疗方法。为了解决这一假设，我们建议 两个具体目标：1)评估年龄对两种右心衰竭模型的影响 RV压力超负荷与低压低氧(肺动脉高压)所致RV 功能障碍，心血管衰老中的一种高度显著和翻译上重要的疾病； 以及2)确定AMPK的激活是否减轻老年小鼠的心功能障碍，以及 发生这种情况的机制。我们将研究AMPK作为一种新型的RV导向的激活 使用遗传和药物方法治疗心脏老化，促进 阐明心脏功能障碍的分子机制。导师团队和 为回答这一翻译上的重要问题而召集起来的职业发展将提供 在衰老生物学、分子遗传学和肌丝力学方面的培训，对于 作为一名独立心脏衰老科学家的职业生涯。共同努力，圆满完成这一任务 提案将通过提供培训、指导和科学研究来推动科学独立 在此指导下，在心脏衰老生物学领域建立成功的研究议程。

ABSTRACT/PROJECT SUMMARY The overarching goal of this application is to provide Dr. Bruns the scientific and career development for a successful independent research career in the field of cardiac aging, with a specific focus on the right ventricle. Heart failure (HF) is a major public health concern within aging populations. In age-related left-sided heart failure as well as other clinical contexts, right ventricular (RV) dysfunction is the strongest predictor of mortality. However, despite the clear link between right heart function and survival, very little is known about RV function with age. This knowledge gap underscores the need to assess the impact of aging on the RV with the long-term goal of developing therapeutics that target declining RV function. Although no RV- directed therapies exist, epidemiological data and preliminary data from our lab suggest that activation of AMP-activated protein kinase (AMPK) may be beneficial through novel and direct action on the cardiac contractile apparatus. Accordingly, the global hypothesis of this project is that aging exacerbates RV dysfunction, and contractile apparatus-mediated mechanisms can be exploited for novel therapies for the aging right heart. To address this hypothesis, we propose two specific aims: 1) to assess the impact of age on two models of right heart failure- isolated RV pressure overload and hypobaric hypoxia (pulmonary hypertension)-induced RV dysfunction, a highly significant and translationally important disease in cardiovascular aging; and 2) to determine if activation of AMPK attenuates cardiac dysfunction in aged mice, and the mechanisms by which this occurs. We will investigate AMPK activation as a novel RV-directed therapy in cardiac aging using both genetic and pharmaceutical approaches, facilitating the elucidation of molecular mechanisms underlying cardiac dysfunction. The mentorship team and career development assembled to answer this translationally important question will provide training in aging biology, molecular genetics, and myofilament mechanics, important skills for a career as an independent cardiac aging scientist. Together, successful completion of this proposal will propel scientific independence by providing the training, mentorship, and scientific guidance upon which to build a successful research agenda in the field of cardiac aging biology.